Sci. STKE, 7 November 2000
Transcription Shifting the Balance
Muscle differentiation is activated by the transcription factor MEF2, which interacts with other transcriptional regulators such as MyoD to promote myogenesis and with histone deactylases (HDAC4 and HDCA5) to inhibit myogenesis. In order for MEF2 to promote myogenesis, there must be a mechanism to shift the balance of these two interactions. McKinsey et al. found that the subcellular distribution of HDAC5 changes from nuclear to cytoplasmic during skeletal muscle differentiation in culture. In transfected Cos cells, activation of calcium-calmodulin kinase (CaMK) I, but not the mitogen-activated protein kinases MKK6, MEK5, or ERK5, or the phosphatase calcineurin, was able to cause the redistribution of HDAC5. Thus, the CaMKI pathway appears to be specific for regulating HDAC, whereas the other MEF2 activators act through a different mechanism. (Stewart and Crabtree describe how the pathways may converge to promote myogenesis.) HDAC5 is phosphorylated in multiple locations by CaMKIV, and the ability of CaMKI to regulate HDAC5 subcellular localization is dependent on two of these sites, one of which is adjacent to the nuclear localization sequence of HDAC5. The importance of this redistribution was demonstrated by showing that transfection of HDAC5 into 10T1/2 fibroblasts inhibited their conversion to muscle by transfected MyoD, and this inhibition was overcome by coexpression of activated CaMKI. Furthermore, HDAC5 without the nuclear localization signal did not inhibit myogenesis, and if the two critical CaMK phosphorylation sites were mutated, then CaMKI was unable to suppress the inhibition caused by transfected HDAC5.
McKinsey, T.A., Zhang, C.-L., Lu, J., and Olson, E.N. (2000) Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408: 106-111. [Online Journal]
Stewart, S., and Crabtree, G.R. (2000) Regulation of the regulators. Nature 408: 46-47. [Online Journal]
Citation: Shifting the Balance. Sci. STKE 2000, tw5 (2000).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882